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1.
Blood ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38875515

RESUMO

The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NFB and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients' clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.

2.
Neurol Neuroimmunol Neuroinflamm ; 11(3): e200229, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38657198

RESUMO

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.


Assuntos
Autoanticorpos , Encefalite , Doença de Hashimoto , Síndromes Paraneoplásicas do Sistema Nervoso , Receptores de GABA-B , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Receptores de GABA-B/imunologia , Encefalite/imunologia , Doença de Hashimoto/imunologia , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/sangue , Estudos Retrospectivos , Adulto Jovem , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Idoso de 80 Anos ou mais
3.
Neurol Neuroimmunol Neuroinflamm ; 11(3): e200228, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38603771

RESUMO

BACKGROUND AND OBJECTIVES: Relapses occur in 15%-25% of patients with leucine-rich glioma-inactivated 1 antibody (LGI1-Ab) autoimmune encephalitis and may cause additional disability. In this study, we clinically characterized the relapses and identified factors predicting their occurrence. METHODS: This is a retrospective chart review of patients with LGI1-Ab encephalitis diagnosed at our center between 2005 and 2022. Relapse was defined as worsening of previous or appearance of new symptoms after at least 3 months of clinical stabilization. RESULTS: Among 210 patients, 30 (14%) experienced a total of 33 relapses. The median time to first relapse was 23.9 months (range: 4.9-110.1, interquartile range [IQR]: 17.8). The CSF was inflammatory in 11/25 (44%) relapses, while LGI1-Abs were found in the serum in 16/24 (67%) and in the CSF in 12/26 (46%); brain MRI was abnormal in 16/26 (62%) relapses. Compared with the initial episode, relapses manifested less frequently with 3 or more symptoms (4/30 patients, 13% vs 28/30, 93%; p < 0.001) and had lower maximal modified Rankin scale (mRS) score (median 3, range: 2-5, IQR: 1 vs 3, range: 2-5, IQR: 0; p = 0.001). The median mRS at last follow-up after relapse (2, range: 0-4, IQR: 2) was significantly higher than after the initial episode (1, range: 0-4, IQR: 1; p = 0.005). Relapsing patients did not differ in their initial clinical and diagnostic features from 85 patients without relapse. Nevertheless, residual cognitive dysfunction after the initial episode (hazard ratio:13.8, 95% confidence interval [1.5; 129.5]; p = 0.022) and no administration of corticosteroids at the initial episode (hazard ratio: 4.8, 95% confidence interval [1.1; 21.1]; p = 0.036) were significantly associated with an increased risk of relapse. DISCUSSION: Relapses may occur years after the initial encephalitis episode and are usually milder but cause additional disability. Corticosteroid treatment reduces the risk of future relapses, while patients with residual cognitive dysfunction after the initial episode have an increased relapse risk.


Assuntos
Encefalite , Humanos , Autoanticorpos , Encefalite/diagnóstico , Imageamento por Ressonância Magnética , Recidiva , Estudos Retrospectivos
4.
Nat Commun ; 14(1): 694, 2023 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-36755036

RESUMO

Type I and III interferons (IFN-I/λ) are important antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDC) are the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCs requires sustained integrin-mediated cell adhesion with infected cells. In turn, pDCs restrict viral spread by an IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likely via a local response at the contact site with infected cells. By exploring the pDC response in SARS-CoV-2 patients, we further demonstrate that pDC responsiveness inversely correlates with the severity of the disease. The pDC response is particularly impaired in severe COVID-19 patients. Overall, we propose that pDC activation is essential to control SARS-CoV-2-infection. Failure to develop this response could be important to understand severe cases of COVID-19.


Assuntos
COVID-19 , Interferon Tipo I , Humanos , SARS-CoV-2/metabolismo , Antivirais/metabolismo , Células Dendríticas/metabolismo , Interferon lambda
5.
J Neurol ; 270(1): 283-299, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36050418

RESUMO

BACKGROUND: The link between paraneoplastic neurological syndromes (PNS) and renal cell and bladder cancer (RCC/BC) is rare and uncertain. Our aim was to clinically evaluate, in light of the updated PNS criteria, these uncommon associations. METHODS: Retrospective nationwide cohort chart review study and systematic review of the literature. RESULTS: After excluding 5 patients due to the diagnosis of another co-occurrent malignancy, 10/18 patients with RCC and 8/18 patients with BC were identified. A total of 31 cases were previously published, yielding an overall series of 27/49 RCC and 22/49 BC patients. There was a predominance of cerebellar syndromes in both cancers (10/27, 37% for RCC; 9/22, 41% for BC), followed by encephalitis in 9/27 (33%) patients with RCC and encephalomyelitis/sensory neuronopathy in 5/22 (23%) patients with BC. The detection of high-risk Abs was more frequent among BC patients (16/19, 84% vs. 3/13, 23% in RCC, p = 0.0009), Ri antibodies being the most frequent thereof. After applying the updated PNS criteria, patients with BC met highest degrees (possible, probable, and definite) of certainty for PNS diagnosis (20/22, 91% vs. 16/27, 59% in RCC, p = 0.021). CONCLUSION: A second neoplasm should always be ruled out before establishing the diagnosis of PNS in patients with RCC or BC. However, while this association remains dubious for most patients with RCC, a casual role is more probable in patients with BC and high-risk antibodies presenting with cerebellar ataxia, brainstem encephalitis or encephalomyelitis/sensory neuronopathy.


Assuntos
Carcinoma de Células Renais , Encefalite , Encefalomielite , Neoplasias Renais , Síndromes Paraneoplásicas do Sistema Nervoso , Síndromes Paraneoplásicas , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células Renais/diagnóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/complicações , Autoanticorpos
6.
Artigo em Inglês | MEDLINE | ID: mdl-35821104

RESUMO

BACKGROUND AND OBJECTIVES: Paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a cancer-related autoimmune disease directed against neural antigens expressed by tumor cells. A putative trigger of the immune tolerance breakdown is genetic alteration of Yo antigens. We aimed to identify the tumors' genetic and immune specificities involved in Yo-PCD pathogenesis. METHODS: Using clinicopathologic data, immunofluorescence (IF) imaging, and whole-transcriptome analysis, 22 breast cancers (BCs) associated with Yo-PCD were characterized in terms of oncologic characteristics, genetic alteration of Yo antigens, differential gene expression profiles, and morphofunctional specificities of their in situ antitumor immunity by comparing them with matched control BCs. RESULTS: Yo-PCD BCs were invasive carcinoma of no special type, which early metastasized to lymph nodes. They overexpressed human epidermal growth factor receptor 2 (HER2) but were hormone receptor negative. All Yo-PCD BCs carried at least 1 genetic alteration (variation or gain in copy number) on CDR2L, encoding the main Yo antigen that was found aberrantly overexpressed in Yo-PCD BCs. Analysis of the differentially expressed genes found 615 upregulated and 54 downregulated genes in Yo-PCD BCs compared with HER2-driven control BCs without PCD. Ontology enrichment analysis found significantly upregulated adaptive immune response pathways in Yo-PCD BCs. IF imaging confirmed an intense immune infiltration with an overwhelming predominance of immunoglobulin G-plasma cells. DISCUSSION: These data confirm the role of genetic alterations of Yo antigens in triggering the immune tolerance breakdown but also outline a specific biomolecular profile in Yo-PCD BCs, suggesting a cancer-specific pathogenesis.


Assuntos
Neoplasias da Mama , Degeneração Paraneoplásica Cerebelar , Anticorpos Antineoplásicos , Autoanticorpos , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Feminino , Humanos , Proteínas do Tecido Nervoso/genética , Degeneração Paraneoplásica Cerebelar/genética
7.
BMJ Open ; 12(4): e056819, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-35393316

RESUMO

INTRODUCTION: Patients with metastatic non-small cell lung cancer (mNSCLC) suffer from numerous symptoms linked to disease and treatment which may further impair the patient's overall condition. In addition to its benefits on quality of life and fatigue, physical exercise may improve treatment response, notably due to its known effects on the immune system. The ERICA study is designed to assess the feasibility of a supervised acute physical exercise therapy realised immediately prior immune-chemotherapy infusion in patients with mNSCLC. Secondary objectives will examine the effects of acute exercise combined with an unsupervised home-walking programme on clinical, physical, psychosocial and biological parameters. METHODS AND ANALYSIS: ERICA is a prospective, monocentric, randomised controlled, open-label feasibility study conducted at the Centre Léon Bérard Comprehensive Cancer Center (France). Thirty patients newly diagnosed with mNSCLC will be randomised (2:1 ratio) to the 'exercise' or the 'control' group. At baseline and during the last treatment cycle, participants in both groups will receive Physical Activity recommendations, and two nutritional assessments. In the exercise group, participants will receive a 3-month programme consisting of a supervised acute physical exercise session prior to immune-chemotherapy infusion, and an unsupervised home-based walking programme with an activity tracker. The acute exercise consists of 35 min interval training at submaximal intensity scheduled to terminate 15 min prior to infusion. Clinical, physical, biological and psychosocial parameters will be assessed at baseline, 3 and 6 months after inclusion. Biological measures will include immune, inflammatory, metabolic, oxidative stress biomarkers and molecular profiling. ETHICS AND DISSEMINATION: The study protocol was approved by the French ethics committee (Comité de protection des personnes Ile de France II, N°ID-RCB 20.09.04.65226, 8 December 2020). The study is registered on ClinicalTrials.gov (NCT number:NCT04676009) and is at the pre-results stage. All participants will sign an informed consent form. The findings will be disseminated in peer-reviewed journals and academic conferences.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/terapia , Exercício Físico , Terapia por Exercício , Estudos de Viabilidade , Humanos , Imunoterapia , Neoplasias Pulmonares/terapia , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Nature ; 600(7890): 701-706, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34673755

RESUMO

Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine1,2, European health authorities recommended that patients under the age of 55 years who received one dose of ChAdOx1-S-nCoV-19 receive a second dose of the Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here we show that the heterologous ChAdOx1-S-nCoV-19 and BNT162b2 combination confers better protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the homologous BNT162b2 and BNT162b2 combination in a real-world observational study of healthcare workers (n = 13,121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody responses, but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential correlated with increased frequencies of switched and activated memory B cells that recognize the SARS-CoV-2 receptor binding domain. The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immunocompromised individuals.


Assuntos
Vacina BNT162/administração & dosagem , Vacina BNT162/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , ChAdOx1 nCoV-19/administração & dosagem , ChAdOx1 nCoV-19/imunologia , SARS-CoV-2/imunologia , Vacinação/estatística & dados numéricos , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Feminino , França/epidemiologia , Hospitais Universitários , Humanos , Memória Imunológica/imunologia , Incidência , Masculino , Células B de Memória/imunologia , Células T de Memória/imunologia , Pessoa de Meia-Idade , Glicoproteína da Espícula de Coronavírus/imunologia
9.
PLoS One ; 16(8): e0255972, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370787

RESUMO

Torque Teno Virus (TTV) is a small, non-enveloped, single-stranded and circular DNA virus that infects the majority of the population worldwide. Increased levels of plasma TTV viral load have been observed in various situations of immune deficiency or dysregulation, and several studies have suggested that TTV levels may be inversely correlated with immune competence. The measurement of TTV viremia by qPCR has been proposed as a potential biomarker for the follow-up of functional immune competence in immunosuppressed individuals, particularly hematopoietic stem cell transplant recipients. We hypothesized that TTV viral load could be used as a prognostic marker of immune checkpoint inhibitor (ICI) efficacy, and therefore investigated the TTV viral load in melanoma patients treated with nivolumab or pembrolizumab before and after 6 months of treatment. In the present study, TTV viral load was not different in melanoma patients before anti-PD-1 introduction compared to healthy volunteers, was not modified by ICI treatment and did not allowed to distinguish patients with treatment-sensitive tumor from patients with treatment-resistant tumor.


Assuntos
Biomarcadores/análise , Infecções por Vírus de DNA/virologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/patologia , Torque teno virus/fisiologia , Carga Viral , Viremia/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Hospedeiro Imunocomprometido , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/virologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
11.
J Exp Med ; 218(10)2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34357402

RESUMO

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3-dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.


Assuntos
Autoanticorpos/imunologia , COVID-19/imunologia , Interferon Tipo I/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Animais , Antivirais/imunologia , Antivirais/farmacologia , Autoanticorpos/sangue , COVID-19/sangue , COVID-19/virologia , Chlorocebus aethiops , Feminino , Humanos , Interferon Tipo I/farmacologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/imunologia , Cavidade Nasal/virologia , Estudos Prospectivos , SARS-CoV-2/fisiologia , Células Vero , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
12.
Sci Immunol ; 6(59)2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035116

RESUMO

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vß21.3 T cell receptor ß chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vß21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vß21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , COVID-19/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Adulto , Criança , Pré-Escolar , Citocinas/sangue , Antígenos HLA-DR/imunologia , Humanos , Ativação Linfocitária/imunologia , SARS-CoV-2/imunologia
13.
J Immunol ; 206(10): 2265-2270, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33931486

RESUMO

NK cells are cytotoxic lymphocytes displaying strong antimetastatic activity. Mouse models and in vitro studies suggest a prominent role of the mechanistic target of rapamycin (mTOR) kinase in the control of NK cell homeostasis and antitumor functions. However, mTOR inhibitors are used as chemotherapies in several cancer settings. The impact of such treatments on patients' NK cells is unknown. We thus performed immunophenotyping of circulating NK cells from metastatic breast cancer patients treated with the mTOR inhibitor everolimus over a three-month period. Everolimus treatment resulted in inhibition of mTORC1 activity in peripheral NK cells, whereas mTORC2 activity was preserved. NK cell homeostasis was profoundly altered with a contraction of the NK cell pool and an overall decrease in their maturation. Phenotype and function of the remaining NK cell population was less affected. This is, to our knowledge, the first in vivo characterization of the role of mTOR in human NK cells.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Everolimo/administração & dosagem , Células Matadoras Naturais/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Seguimentos , França/epidemiologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento
14.
Elife ; 102021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33507150

RESUMO

Antiviral effectors such as natural killer (NK) cells have impaired functions in chronic hepatitis B (CHB) patients. The molecular mechanism responsible for this dysfunction remains poorly characterised. We show that decreased cytokine production capacity of peripheral NK cells from CHB patients was associated with reduced expression of NKp30 and CD16, and defective mTOR pathway activity. Transcriptome analysis of patients NK cells revealed an enrichment for transcripts expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion employ common mechanisms. In particular, the transcription factor TOX and several of its targets were over-expressed in NK cells of CHB patients. This signature was predicted to be dependent on the calcium-associated transcription factor NFAT. Stimulation of the calcium-dependent pathway recapitulated features of NK cells from CHB patients. Thus, deregulated calcium signalling could be a central event in both T cell exhaustion and NK cell dysfunction occurring during chronic infections.


Assuntos
Fatores de Restrição Antivirais/imunologia , Hepatite B Crônica/imunologia , Células Matadoras Naturais/imunologia , Infecção Persistente/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Nat Commun ; 11(1): 5341, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087723

RESUMO

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade/genética , Proteína 1 Supressora da Sinalização de Citocina/deficiência , Proteína 1 Supressora da Sinalização de Citocina/genética , Adolescente , Adulto , Idade de Início , Doenças Autoimunes/metabolismo , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Haploinsuficiência , Humanos , Masculino , Modelos Moleculares , Mutação , Linhagem , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/química , Linfócitos T/imunologia
19.
J Leukoc Biol ; 106(6): 1349-1358, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31568613

RESUMO

Dendritic cells (DC) from diabetes-prone NOD mice and patients with type 1 diabetes (T1D) produce excess IL-12 that drives development of ß-cell-destroying IFN-γ-producing T cells. The molecular mechanisms that control IL-12 production in T1D are unclear. In this study, we report that ß-catenin, a multifunctional protein involved in inflammation, is dramatically increased in DC from NOD mice. We further investigated the mechanisms leading to accumulation of ß-catenin in NOD DC and its role in the inflammatory pathogenic responses associated with T1D. Hyperphosphorylation of ß-catenin at a stabilizing residue, serine 552, mediated by activation of Akt, appears to lead to ß-catenin accumulation in NOD DC. Elevated ß-catenin in DC correlated with IL-12 production and induction of IFN-γ-producing CD4 cells. On the one hand, knockdown/inhibition of ß-catenin significantly reduced NOD DC production of IL-12 and their ability to induce IFN-γ-producing CD4 cells. On the other hand, overexpression of ß-catenin in control DC resulted in increased IL-12 production and induction of IFN-γ-production in T cells. Additionally, we found that ß-catenin inhibitors decreased NF-κB activation in NOD DC and IFN-γ production by NOD T cells in vivo. These data strongly suggest that accumulation of ß-catenin in DC from NOD mice drives IL-12 production, and consequently, development of pathogenic IFN-γ-producing T cells. Targeting the defect responsible for ß-catenin accumulation and subsequent overproduction of pro-inflammatory cytokines by NOD DC could be an effective therapeutic strategy for the prevention and/or treatment of T1D.


Assuntos
Células Dendríticas/metabolismo , Interferon gama/biossíntese , Interleucina-12/biossíntese , Subpopulações de Linfócitos T/metabolismo , beta Catenina/metabolismo , Animais , Biomarcadores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos NOD , NF-kappa B/metabolismo , Fosforilação , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , beta Catenina/antagonistas & inibidores
20.
Cytokine ; 113: 446-452, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30413290

RESUMO

Type I interferonopathies are characterized by an increase of circulating type I interferon (IFN) concentration. Type I interferonopathies refer to rare Mendelian genetic disorders such as Aicardi-Goutières Syndrome (AGS) as well as more frequent and polygenic auto-immune diseases like systemic lupus erythematosus (SLE). Yet, detection of type I IFN in these patients remains challenging as its amount is usually very low in patients' sera. Thus, the detection of interferon-stimulating genes has been proposed as an alternative for the detection of this cytokine but sensitivy, specificity and predictive values of the assay have not been reported so far. In this study, we propose two different methods based on Nanostring or RT-qPCR to measure in the clinical routine the IFN response, defined as a set of transcripts that are systemically induced by IFNs. The IFN signature is composed of 6 IFN stimulated genes (ISGs) and has a strong predictive value for the diagnosis of type I interferonopathies. The use of this simple test might represent a gold standard for the evaluation of various autoimmune diseases. Moreover, this test could also be used to monitor patients treated with drugs targeting type I IFN pathway. When comparing both methods - Nanostring and qPCR - in terms of analytical performance, they provided similar results but Nanostring was quicker, easier to multiplex, and almost fully-automated, which represent a more reliable assay for the daily clinical practice.


Assuntos
Doenças Autoimunes do Sistema Nervoso , Regulação da Expressão Gênica , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico , Malformações do Sistema Nervoso , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/metabolismo , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/metabolismo
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